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The Journal of Neuroscience, January 7, 2004, 24(1):43-52; doi:10.1523/JNEUROSCI.2528-03.2004

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Development/Plasticity/Repair
The Secretory Granule-Associated Protein CAPS2 Regulates Neurotrophin Release and Cell Survival

Tetsushi Sadakata,^1,4 Akira Mizoguchi,⁵ Yumi Sato,¹ Ritsuko Katoh-Semba,⁶ Mitsunori Fukuda,² Katsuhiko Mikoshiba,^3,4 and Teiichi Furuichi¹

¹Laboratory for Molecular Neurogenesis, ²Fukuda Initiative Research Unit, and ³Laboratory for Developmental Neurobiology, RIKEN Brain Science Institute, Wako, Saitama 351-0198, Japan, ⁴Department of Molecular Neurobiology, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan, ⁵Department of Anatomy, School of Medicine, Mie University, Tsu, Mie 514-8507, Japan, and ⁶Department of Perinatology, Institute for Developmental Research, Aichi Human Service Center, Kasugai, Aichi 480-0392, Japan

Neurotrophins are key modulators of various neuronal functions, including differentiation, survival, and synaptic plasticity, but the molecules that regulate their secretion are poorly understood. We isolated a clone that is predominantly expressed in granule cells of postnatally developing mouse cerebellum, which turned out to be a paralog of CAPS (Ca²⁺-dependent activator protein for secretion), and named CAPS2. CAPS2 is enriched on vesicular structures of presynaptic parallel fiber terminals of granule cells connecting postsynaptic spines of Purkinje cell dendrites. Vesicle factions affinity-purified by the CAPS2 antibody from mouse cerebella contained significant amounts of neurotrophin-3 (NT-3), brain-derived neurotrophic factor (BDNF), and chromogranin B but not marker proteins for synaptic vesicle synaptophysin and synaptotagmin. In cerebellar primary cultures, punctate CAPS2 immunoreactivities are primarily colocalized with those of NT-3 and BDNF and near those of a postsynaptic marker, postsynaptic density-95, around dendritic arborization of Purkinje cells. Exogenously expressed CAPS2 enhanced release of exogenous NT-3 and BDNF from PC12 cells and endogenous NT-3 from cultured granule cells in a depolarization-dependent manner. Moreover, the overexpression of CAPS2 in granule cells promotes the survival of Purkinje cells in cerebellar cultures. Thus, we suggest that CAPS2 mediates the depolarization-dependent release of NT-3 and BDNF from granule cells, leading to regulation in cell differentiation and survival during cerebellar development.

Key words: neurotrophin; BDNF; NT-3; granule cell; Purkinje cell; parallel fiber; cerebellum; CAPS; exocytosis; secretory granule

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Received May 21, 2003; revised November 5, 2003; accepted November 5, 2003.

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